Heparin Induced Thrombocytopenia

Heparin Induced Thrombocytopenia – Introduction

There are two forms of heparin-induced thrombocytopenia (HIT).
Type I HIT is a mild, transient decrease in platelet count that occurs during the first 2 days of heparin exposure due to non–immune-mediated platelet aggregation.
This is a benign reaction, and the platelet count will return to normal while heparin is continued. This chapter will address type II HIT, an antibody-mediated thrombocytopenia with risk of thrombosis.

Synonyms

Type II heparin-induced thrombocytopenia
Heparin-induced thrombocytopenia and thrombosis (HITT)
Heparin-associated immune thrombocytopenia

ICD-10CM CODE
D75.82	Heparin-induced thrombocytopenia (HIT)

Epidemiology & Demographics

Incidence

Occurs in 0.1% to 5% of patients exposed to heparin in various clinical settings.

Predominant Sex & Age

Initial studies showed increased risk in females; however, more recent studies demonstrate increased risk among males.
Patients with age >50 yr are more likely to be diagnosed with HIT, with each increasing year of age conferring slightly higher risk of HIT. ¹ ^, 2

Risk Factors

Heparin type (LMWH has relative risk reduction of 77% compared with UFH), dose (therapeutic dose may have a greater risk than prophylactic dose, though no dose is considered too low to cause HIT), and duration (longer duration of exposure confers greater risk); type of patient (surgical patients, especially cardiac and orthopedic, are at higher risk than medical patients). ² ^, 3
Risk factors for HIT are summarized in Table E1.

TABLE E1

Risk Factors for Heparin-Induced Thrombocytopenia

From Hoffman R et al: Hematology: basic principles and practice, ed 7, Philadelphia, 2018, Elsevier.

Heparin Type	Unfractionated > Low-Molecular-Weight Heparin > Fondaparinux
Patient type	Postoperative (major > minor surgery) > medical > obstetric/pediatric
Dose ^a	Prophylactic dose > therapeutic dose > flushes
Duration	11-14 days ^b> 5-10 days > 4 days or fewer
Sex	Female > male

Physical Findings & Clinical Presentation

Suspect in a patient with:

•Exposure to heparin in prior 3 mo, especially if initiated in the last 5 to 10 days.
•Platelet count decrease to 50% below pretreatment baseline; 5% of patients will not become thrombocytopenic despite this reduction.
•Venous or arterial thrombosis occurs in about 50% of patients without prompt treatment (e.g., deep vein thrombosis [DVT], pulmonary embolism [PE], skin necrosis at heparin injection sites, limb gangrene, stroke or cavernous sinus thrombosis, myocardial infarction).
•Bleeding occurred in ∼6% of HIT patients, half of which was GI bleed. ²
•Acute anaphylaxis during administration of heparin bolus.

Etiology

Occurs when immunoglobulin G (IgG) antibodies bind to complexes of heparin and platelet factor 4 (PF4), a prothrombotic cytokine released from platelets during their activation. The resulting immune complexes activate adjacent platelets, leading to further PF4 release, additional antibody production, and eventual platelet aggregation with premature removal from circulation (causing thrombocytopenia). This process also leads to increased thrombin generation, though the full mechanism of thrombosis in HIT is not completely understood. ¹

Differential Diagnosis

Thrombocytopenia due to other causes including:

•Sepsis or infection
•Disseminated intravascular coagulation
•Immune thrombocytopenia
•Thrombocytopenic thrombotic purpura
•Hemolytic uremic syndrome
•Drug-induced thrombocytopenia (other than heparin)
•Antiphospholipid antibody syndrome
•Liver failure
•Splenic sequestration
•Intravascular devices

Workup

HIT is, first and foremost, a clinical diagnosis that is confirmed with laboratory testing. The 4T score translates clinical findings to pretest probability as outlined in Table E2 . If the patient has a low pretest probability score, then there is no need for further testing. Moderate or high pretest probability warrants laboratory tests for HIT ( Table E3 ).

TABLE E2

The 4Ts Score for Estimating the Pretest Probability of Heparin-Induced Thrombocytopenia

From Vincent JL et al: Textbook of critical care, ed 7, Philadelphia, 2017, Elsevier.

	POINTS (0, 1, or 2 for each of the four parameters; maximum points = 8)
	2	1	0
Thrombocytopenia (acute)	>50% platelet count fall to nadir ≥20 × 10 ⁹/L	30%-50% platelet count fall; or nadir 10-19 × 10 ⁹/L	<30% platelet count fall; or nadir ≤10 × 10 ⁹/L
Timing of fall in platelet count or other sequelae	Onset day 5-10 or <1 day (if heparin exposure within 30 days)	>Day 10, timing unclear, or <day 1 with recent heparin 31-100 days	Platelet count fall <day 4 (without recent heparin exposure)
Thrombosis or other sequelae	New thrombosis; skin necrosis; post–heparin bolus acute systemic reaction	Progressive or recurrent thrombosis; erythematous skin lesions; suspected thrombosis—not confirmed	None
Other cause for thrombocytopenia	No other cause for platelet count fall is evident	Possible other cause is evident	Definite other cause is present
Pretest probability score: 6-8 = High; 4-5 = Intermediate; 0-3 = Low

TABLE E3

Laboratory Assays for Heparin-Induced Thrombocytopenia

From Goldman L, Schafer AI: Goldman’s Cecil medicine, ed 24, Philadelphia, 2012, Saunders.

Assay	Sensitivity (%)	Specificity (%)	Positive Predictive Value (%)	Negative Predictive Value (%)
Functional assay (e.g., serotonin release assay)	88	∼100	∼100	81
PF4/heparin enzyme immunoassay (ELISA)	95-98	86	93	95

ELISA, Enzyme-linked immunosorbent assay; PF4, platelet factor 4.

Laboratory Tests

These can be broadly divided into two categories: Immunoassays (high sensitivity) and functional assays (high specificity). ⁴

Immunoassay testing for HIT antibodies with an enzyme-linked immunosorbent assay (ELISA) is very sensitive, but not specific. The majority of patients with HIT antibodies will not develop clinical HIT. Thus, HIT antibody testing is more effective for ruling out rather than confirming the diagnosis of HIT. ³ ^,⁴

Result of the previously mentioned immunoassay is reported as HIT antibody optical density (OD), which divides into the following categories: Weakly positive (0.4 to 1.0), moderately positive (1.0 to 2.0), and strongly positive (>2.0). A weakly positive OD is rarely associated with functional assay positivity (1% to 5%), whereas an OD >2.0 almost always shows functional assay positivity (89% to 100%). Of note, the HIT antibody IgG subtype is the pathologic antibody for HIT; therefore, the use of immunoglobulin G (IgG)-specific ELISA kits increases the test specificity over the polyspecific (IgA/M/G) antibody. ³⁴⁵

Negative and strongly positive HIT antibody immunoassay results are usually sufficient to either exclude or confirm HIT diagnosis, respectively. As for weakly or moderately positive results, however, the functional serotonin release assay (14C-SRA) is often pursued. This test is the gold standard for HIT that measures heparin-dependent platelet activation.

Donor platelets are radiolabeled with serotonin and then incubated with patient serum and heparin. If antibodies to the platelet factor 4–heparin complex are present in the patient’s serum, the platelets react and release the radiolabeled serotonin, which is then measured. Result of this test ultimately confirms or excludes the diagnosis. Availability and turnaround time of this test is dependent on the institution, and this often limits the test’s clinical utility.

Heparin-induced platelet aggregation test, flow cytometry, or even combining multiple immunoassays with 4Ts score show promising data to obtain confirmatory data more readily, but their routine utilization is yet premature. ³⁴⁵

Overall, the diagnosis of HIT is confirmed by (1) a strongly positive ELISA or (2) a positive functional assay. It is excluded by (1) low pretest probability on 4Ts, (2) negative ELISA, or (3) a negative functional assay.

Recently, a combination score of the latex immunoturbidimetric assay (LIA) that assesses competitive inhibition of an HIT-like monoclonal antibody and a chemiluminescence immunoassay (CLIA) that detects anti-PF4/heparin IgG has been developed.

The LIA and CLIA tests are individually scored from 0 to 3 based on the results. Points are given as follows: Weak-positive result (1.00 to 4.99 U/ml) = 1 point; moderate-positive result (5.00 to 15.9 U/ml) = 2 points; and strong-positive result (≥16.0 U/ml) = 3 points.

Total points can range from 0 to 6. LIA/CLIA has shown high sensitivity (about 99%) equivalent to immunoassays described previously. LIA/CLIA score ≥4 also has high specificity (98%) comparable to 14C-SRA functional assay. Along with comparable sensitivity/specificity to existing immunoassays/functional assays, the major advantage of LIA/CLIA test is the turnaround time of the combination test; results of LIA are available in about 20 min, and results of CLIA are available in about 30 min. ⁶

Imaging Studies

DVT screening with bilateral low extremity ultrasound is recommended for all suspected HIT with further imaging (e.g., upper extremity ultrasound) considered for appropriate clinical setting. ³

Treatment

•For patients with a moderate or high pretest probability from 4Ts, discontinue all heparin exposure. Even if the patient does not have a clinically evident thrombosis, there is a significant risk of developing an incident clot within the subsequent 30 days. Thus, the patient must be started on an alternative anticoagulant.
•Two agents, both direct thrombin inhibitors, are approved for this indication ( Table E4 ):
- 1.Argatroban (preferred agent in renal failure and in hemodialysis patients; avoid in liver dysfunction).
- 2.Bivalirudin (approved only for patients with HIT or at risk of HIT who are undergoing PCI; dose adjustment is required in renal failure).
•Note: Lepirudin is no longer available. Outside of the U.S., the factor Xa inhibitor danaparoid may be used.
•Platelet transfusion in the absence of life-threatening hemorrhage or extreme thrombocytopenia should be avoided. Risk of bleeding is low, and platelet transfusions in HIT can increase risk of arterial thrombosis. ³
•In patients with critical illness, high risk of bleeding, need for urgent procedures, or HIT that is complicated by life- or limb-threatening venous thromboembolism (VTE), argatroban and bivalirudin are recommended due to their shorter duration of action. ³
•For relatively stable patients with average risk of bleeding, direct oral anticoagulants (DOACs) and fondaparinux may be considered. ³
•Warfarin should not be initiated until after platelet counts recover to >150 × 10 ⁹/L because there is increased risk of warfarin-induced skin necrosis and venous limb gangrene. In a patient who is diagnosed with HIT while on warfarin, vitamin K should be administered with concomitant initiation of nonheparin anticoagulant. ³
•The length of treatment is controversial, but most clinicians agree that at least 1 mo of alternative anticoagulation is required in the absence of thrombosis, while at least 3 to 6 mo of treatment are required in the presence of thrombosis.
•Fondaparinux, a synthetic pentasaccharide that inhibits factor X but not thrombin, is being increasingly used for treatment of HIT despite not yet being FDA approved ( Table E5 ). Observational data suggest it has similar efficacy as direct thrombin inhibitors, with the additional advantages of lower bleeding risk, easier administration (subcutaneous), and lower cost. ⁷ Rare cases of fondaparinux-induced HIT have been reported, however.
•The use of direct oral anticoagulants (e.g., rivaroxaban, dabigatran, apixaban) is more commonly used. They are reasonable options in relatively stable patients with average risk of bleeding. When DOACs are used, VTE treatment dosing regimen should be used. ³
•In patients with confirmed HIT, all heparin products should be avoided for life. A possible exception is in patients who require brief intraoperative anticoagulation such as cardiac bypass surgery.

TABLE E4

Treatment Schedules for Bivalirudin and Argatroban

Dosing protocols shown are appropriate for most patients with strongly suspected or confirmed HIT whether or not complicated by thrombosis. (Dosing for bivalirudin and argatroban is substantially different when given for PCI.) aPTT, Activated partial thromboplastin time; HIT, heparin-induced thrombocytopenia; INR, international normalized ratio; PCI, percutaneous coronary intervention.Modified from Hoffman R et al: Hematology: basic principles and practice, ed 7, Philadelphia, 2018, Elsevier.

Anticoagulant	Dosing Protocol for HIT-Associated Thrombosis	Anticoagulant Monitoring ^a	Clearance	Half-Life (min)	Comment
Bivalirudin	No bolus; initial infusion rate: 0.15-0.20 mg/kg/h	1.5-2.5 × baseline aPTT	Enzymic (80%); renal (20%)	25	Off-label treatment for HIT (although approved for PCI in patient with HIT); minor prolongation of INR (compared with argatroban)
Argatroban	No bolus; initial infusion rate: 2 μg/kg/min	1.5-3.0 × baseline aPTT	Hepatobiliary	40-50	Initial dose 0.5 μg/kg/min in hepatic insufficiency ^b; moderate or marked prolongation of INR, which complicates overlap with warfarin anticoagulation

TABLE E5

Treatment Schedules for Danaparoid and Fondaparinux

HIT, Heparin-induced thrombocytopenia; IV, intravenous.From Hoffman R et al: Hematology: basic principles and practice, ed 7, Philadelphia, 2018, Elsevier.

Anticoagulant	Therapeutic Dosing Protocol for HIT-Associated Thrombosis ^a	Anticoagulant Monitoring	Clearance	Half-Life (h)	Comment
Danaparoid	Initial bolus, 2250 units ^bIV; accelerated infusion (400 units/hr × 4 h, 300 units/hr × 4 h; then 200 units/h IV, subsequently adjusted by antifactor Xa levels)	Antifactor Xa levels (target, 0.5-0.8 units/ml)	Renal (minor)	25	Widely approved for HIT treatment (although not in the U.S.); not available in the U.S.; low risk for in vivo cross-reactivity; prophylactic-dose therapy ^cmay be appropriate when clinical suspicion for HIT is low.
Fondaparinux	7.5 mg ^dsubcutaneous once daily	Anti–Xa factor levels (target levels not well established)	Renal (major)	17	Not approved for HIT treatment (although increasingly used as off-label therapy). Prophylactic-dose therapy ^emay be appropriate when clinical suspicion for HIT is low, or if there is renal insufficiency.

Referral

Request a hematology consultation.

Pearls & Considerations

•HIT paradoxically causes thrombocytopenia and clotting. Bleeding is much less common.
•It is unclear whether patients with HIT should be considered heparin allergic lifelong. Risk of recurrent HIT with heparin rechallenge year later is relatively low, ∼5% in one small study (though recurrence risk is higher perioperatively). ⁸ If such a patient requires surgery with heparin (e.g., on-pump cardiac bypass), consider perioperative argatroban.
•Consult the coagulation laboratory and/or hematology when bridging patients on argatroban to warfarin, as argatroban concomitantly raises the international normalized ratio in most assays. Some clinicians will use a higher target than 2 to 3 during the bridging period for this reason.
•Be alert to heparin exposure in the absence of anticoagulation or DVT prophylaxis: Hospitalized patients are often exposed to heparin lock flushes, heparin-coated catheters, or heparin-coated guidewires—any of which could precipitate HIT.

Prevention

Strongly consider the use of low-molecular-weight heparin in place of unfractionated heparin in hospitalized patients with a stable creatinine clearance of 30 ml/min or greater. Such a preventive strategy can reduce the risk of HIT by over 90% and yield cost savings in testing and treatment.

References

1.Hogan M., Berger J.S.: Heparin-induced thrombocytopenia (Hit): review of incidence, diagnosis, and management . Vasc Med 2020; 25 (2): pp. 160-173.

2.Dhakal B., et al.: Disease burden, complication rates, and health-care costs of heparin-induced thrombocytopenia in the USA: a population-based study . Lancet Haematol 2018; 5 (5): pp. e220-e231.

3.Cuker A., et al.: American Society of Hematology 2018 guidelines for management of venous thromboembolism: heparin-induced thrombocytopenia . Blood Adv 2018; 2 (22): pp. 3360-3392.

4.Pishko A.M., Cuker A.: Diagnosing heparin-induced thrombocytopenia: the need for accuracy and speed . Int J Lab Hematol 2021; 43 (Suppl 1): pp. 96-102.

5.Warkentin T.E.: Challenges in detecting clinically relevant heparin-induced thrombocytopenia antibodies . Hamostaseologie 2020; 40 (4): pp. 472-484.

6.Warkentin T.E., et al.: Combination of two complementary automated rapid assays for diagnosis of heparin-induced thrombocytopenia (Hit) . J Thromb Haemost 2020; 18 (6): pp. 1435-1446.

7.Schindewolf M., et al.: Use of fondaparinux off-label or approved anticoagulants for management of heparin-induced thrombocytopenia . J Am Coll Cardiol 2017; 70 (21): pp. 2636-2648.

8.Warkentin T.E., Anderson J.A.M.: How I treat patients with a history of heparin-induced thrombocytopenia . Blood 2016; 128 (3): pp. 348-359.